1. Field of the Invention
This is a 371 of PCT/DE02/04302, filed Nov. 22, 2002, and published as WO 03/045895 on Jun. 5, 2003.
The invention relates to a process for obtaining 5-bromo levulinic acid methyl ester from a bromination mixture, which is obtained by bromination of levulinic acid or levulinic acid methyl ester and which contains 5-bromolevulinic acid methyl ester, and to a process for obtaining 5-chlorolevulinic acid alkyl esters.
The bromination of levulinic acid in methanol with one mol equivalent of bromine yields    1. 3-bromolevulinic acid methyl ester    2. 5-bromolevulinic acid methyl ester    3. 3,5-bromolevulinic acid methyl esterand as a result of the consumption of further bromine equivalents for the formation of 3,5-bromolevulinic acid methyl ester from (1) and/or (2)    4. the not brominated levulinic acid methyl ester.
The quantity ratio of the products within the bromination mixture behaves like (1):(2):(3):(4)=28:56:8:8, whereas insignificant variations may occur according to the reaction conditions. In general, however, the selectivity of the formation of the bromination products, especially the 5-bromolevulinic acid methyl ester, can not decisively be changed. The bromination of levulinic acid methyl ester (4) instead of levulinic acid with one equivalent of bromine in methanol leads approximately to the same result.
2. Description of the Prior Art
Therefore, the production of 5-bromolevulinic acid methyl ester depends on the mentioned bromination mixture. According to the latest development of the technology, several processes for the isolation of the 5-bromolevulinic acid methyl ester from the bromination mixture are known.
S. F. McDonald in Can. J. Chem. 1974, 52, 3257–3258 describes a process, from which the mentioned bromine compound is obtained from the bromination mixture by double fractional high vacuo distillation. In this way the 5-bromolevulinic acid methyl ester is obtained (relating to the starting compound levulinic acid) in 30% yield and about 2% of the 3,5-dibromolevulinic acid methyl ester as an impurity.
To prevent an acid catalysed change of the ratio of the isomers, the destination should proceed quickly and the thermal stress of the bromination mixture should be kept as low as possible. A higher thermal strain particularly has a problematic effect if traces of hydrogen bromide are present, which cause an unfavourable change of the yield to the disadvantage of the 5-bromolevulinic acid methyl ester. The experience also showed, that the amount of the 5-bromolevulinic acid methyl ester obtained by fractional distillation, considerably decreases, if small amounts of the 3,5-dibromolevulinic acid methyl ester are present.
The requirements for the careful production of the desired ester connected with an optimal yield are met only unsufficiently, since the double fractional distillation causes a comparable high expenditure of time resulting in a high thermal strain of the distillation mixture.
Moreover, if the range of pressure needed for the distillation is not reached within a short period of time, the destination time is lengthend and on top the thermal strain of the bromination mixture increases.
On top of that, it especially has to be considered as a disadvantage, that the separation of the brominated products by distillation according to the available process all in all is very expensive, because for this a double fractional distillation using a vacuum jacketed vigreux column is necessary. Because of the high technical expense, this process is ruled out for a large-scale application.
H.-J. Ha, S.-K. Lee, Y.-J. Ha, J. W. Park, Synth. Comm. 1994, 24(18), 2557–2562 describe a process for obtaining 5-bromolevulinic acid methyl ester, which provides the desired ester from the bromination mixture by means of column chromatography. High costs are connected in an unfavourable manner to this process and therefore a purification using liquid chromatography is out of question when you consider a technical application.
With regard to the use of 5-bromolevulinic acid methyl ester, production processes for the preparation of 5-aminolevulinic acid hydrochloride must be mentioned in the latest development of the technology.
American patent U.S. Pat. No. 5,907,058 shows a process in which 5-aminolevulinic acid hydrochloride is prepared by processing 5-bromolevulinic acid methyl ester with sodium diformylamide in water-free acetonitrile and the following acid catalysed hydrolysis of the resulting 5-diformylamino levulinic acid methyl ester.
In the Z. Naturforsch. 1986, 41b, 1593–1594 a process is described by E. Benedikt and H.-P. Köst, which is characterised by the following steps: Processing of 5-bromolevulinic acid methyl ester together with potassium phthalimide in dimethylforamide yielding 5-phthalimido levulinic acid methyl ester, which is then hydrolised by an acid.
Finally, in the above mentioned publication of H.-J. Ha, S.-K. Lee, Y.-J. Ha, J. W. Park, Synth. Comm. 1994, 24(18), 2557–2562, a process for the preparation of 5-aminolevulinic acid hydrochloride is described. This process starts with 5-bromolevulinic acid methyl ester, which is prepared from levulinic acid by bromination, and which is characterised by the following process steps: Processing of 5-bromolevulinic acid methyl ester together with sodium azide in dimethyl formamide to 5-azidolevulinic acid methyl ester and followed by the catalytic hydrogenation and the subsequent ester hydrolysis of the formed 5-aminolevulinic acid methyl ester hydrochloride.
The disadvantage of these processes is, that they require the starting material in high purity. The herewith connected high technical expense and the high costs for the preparation of this product lead to the fact, that a large-scale production of 5-aminolevulinic acid hydrochloride like mentioned above is unprofitable so far.